Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences.

Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I. Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M1dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 micromol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141 nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M1dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.     

Association of polymorphisms in the paraoxonase 1 gene with breast cancer incidence in the CPS-II Nutrition Cohort.

Paraoxonase 1 (PON1) plays an important role in the high-density lipoprotein-mediated prevention of low-density lipoprotein oxidation and the metabolism of lipid-soluble radicals. In this study, we investigated the association of two common, nonsynonymous polymorphisms in the PON1 gene (Q192R and L55M) with breast cancer risk in postmenopausal women through a nested case-control study within the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Using conditional logistic regression of genotyping results from 502 cases and 502 cancer-free controls matched on age, race/ethnicity, and date of blood draw, we found that the L55M single nucleotide polymorphism (SNP) was associated with an increased risk of breast cancer [odds ratio (OR), 1.58; 95% confidence interval (95% CI), 1.05-2.37 for MM]. No association was found for the Q192R SNP. The L55M association with breast cancer was modified by nonsteroidal anti-inflammatory drug (NSAID) use. The association was limited to women who took NSAIDs and was somewhat stronger among women who reported regular (> or = 15 times per month) NSAID use (OR, 3.24; 95% CI, 1.17-9.00) than in those who reported any NSAID use (OR, 2.46; 95% CI, 1.39-4.36). These results suggest that genetic variation in PON1, particularly at the L55M SNP, may be associated with increased risk of breast cancer in postmenopausal women. Furthermore, NSAID use seems to modify this risk.     

Cutaneous metastases of lung cancer

It is uncommon for a cancer to be diagnosed because of skin metastases. Cutaneous metastases as initial manifestation of internal neoplasias, represent only 0.8% of total cases and implies, in general, a very advanced grade of the disease and short survival. When skin metastases of an unknown primary site appear, lung cancer is the first option to be discarded in case of men, and breast cancer in case of women. Lung cancer spreads to the skin in 2.8–8.7% of the cases, in advanced phases of the disease, although just in 7–23.8% of the cases, cutaneous metastases appear as first manifestation of the primary tumor. Sometimes, a complete examination to discover the tumor reveals no metastases elsewhere.     

Impact of neoadjuvant hormonal therapy on dose-volume histograms in patients with localized prostate cancer under radical radiation therapy

Introduction Prostate volume involves a defined toxicity predictor in the radiation therapy of localized prostate cancer. Neoadjuvant hormone therapy (nHT) can reduce prostate volume and, therefore, the planned volume. The objective of this study was to establish if the value of nHT reduces the planned volume and if this reduction correlates with a reduction of the dose received in the target organs. Material and methods 28 patients diagnosed of localized prostate cancer and referred to our departments for radiation therapy with radical intention, in the period ranging between April 2002 and October 2003, were included prospectively. The patients received nHT (triptorelin+flutamide) for 2 months and adjuvant HT until completing 2 years in the high-risk cases. A transrectal ultrasound study was performed in all patients, simulation CT and planning before the start of HT and after 2 months of treatment. The radiation therapy was carried out with 6 or 18 MV LINAC photons, with a dose fractioning scheme of 5×180–200 cGy, a total dosage of 66–72 Gy to prostate, 56 Gy to seminal vesicles and, in the high-risk cases, 46 Gy to pelvic lymph nodes. Results The distribution according to risk group was: low risk 3.6%, intermediate risk 28.6% and high risk 67.9%. By transrectal ultrasound, prostate volume on diagnosis was 50.65 cc pre HT and 38.97 cc post HT (p<0.001), which means a volume reduction of 24%. The comparative analysis of the dose-volume histograms of the first versus the second CT shows a reduction in the planned volume GTV1 (prostate) (81.33 cc vs 63.96 cc, p<0.05), PTV1 (prostate and margin) (197.51 cc vs 168.38 cc, p<0.001) and PTV2 (prostate, vesicles and margin) (340.5 cc vs 307.26 cc, p<0.05), a reduction of the maximum dose in the seminal vesicles (70.2 versus 68.75 Gy, p<0.05), a reduction of the mean dose in the seminal vesicles (65.07 Gy versus 63.07 Gy, p<0.05), PTV2 (67.72 Gy versus 66.9 Gy, p<0.01) and PTV3 (prostate, vesicles, pelvic lymph nodes and margin) (58.86 Gy versus 57.21 Gy, p<0.01), a reduction of the D90 in the seminal vesicles (61.83 Gy versus 60.06 Gy, p<0.05) and PTV2 (61.04 Gy versus 59.45 Gy, p<0.05) and a reduction of V60 of the rectum (32.45% versus 28.22%, p<0.05) and V60 of the bladder (41.78% versus 31.67%, p<0.005). Conclusions Neoadjuvant hormone therapy reduces significantly prostate volume and as a result the planned volume and consequently the rectal and bladder V60 can be significantly reduced.     

Cooperative role of telomerase activity and p16 expression in the prognosis of non-small-cell lung cancer.

PURPOSE: Telomerase activity and p16 expression can be considered two of the most important molecular markers implicated in tumorigenesis. Our main aim was to study the cooperative role of both molecular alterations in the prognosis of patients surgically resected for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We have determined telomerase activity and p16 expression in a series of 98 prospectively collected NSCLC specimens obtained from patients who had undergone surgery without other treatment. Telomerase activity was investigated by a telomeric repeat amplification protocol enzyme-linked immunosorbent assay-based procedure, and p16 expression was examined by Western blot. Associations with survival were evaluated. RESULTS: Positive results for telomerase activity were found in 82% of the cases, and this variable correlated with poor differentiation and recurrence of tumors. Lack of p16 expression was observed in 61% of tumors, and a significant association with tumor recurrence was also observed. By univariate analysis, both negative telomerase activity and p16-positive expression were significantly correlated with a better prognosis. Moreover, statistics for equality of survival distributions for telomerase, adjusted for p16, indicated a positive interaction between both parameters. For telomerase-positive tumors, p16 expression emerged as a significant independent protective variable, as indicated by Cox multivariate analysis (relative risk [RR], 0.214; P =.014). This protective effect was maintained only for stage I and II tumors (RR, 0.108; P =.046). CONCLUSION: These results suggest that the combined telomerase activity and p16 expression analyses may be of prognostic importance in NSCLC, especially for patients affected by stage I and II tumors.     

Experiencia en la implementación de un protocolo de verificación de la tasa de Kerma de referencia en aire de semillas de125I

This paper presents the experience in the use of a validation protocol for the¹²⁵I seeds reference air Kerma rate used in prostate treatments before being implanted. The method used employs a well-type ionization chamber that has been calibrated against an international standard at an accredited dosimetry calibration laboratory (ADCL), this is a direct traceability system. Then, as a quality control check on the well-chamber’s response, the calibration factors are assayed on an ADCL calibrated¹²⁵I seed, secondary traceability system. Before each assay procedure a long-lived source, which dosimetric characteristics are well known, is placed in the well-chamber as a redundancy program to verify that our dosimetry system has not changed with time. Finally the results of verifications over a 2-year period are discussed.     

Impact of hematological diagnosis on early and late outcome after laparoscopic splenectomyrid=""

Background: Laparoscopic splenectomy (LS) is now regarded as the treatment of choice for autoimmune thrombopenia (ITP). However, there have been few reports describing the application of LS to other splenic diseases, such as malignant entities and conditions associated with splenomegaly. Hematological diseases have specific clinical features that can influence immediate outcome after LS. Although the long-term effects of LS are unknown, a risk of splenosis has been suggested. Therefore, we designed a study to analyze the impact of primary hematological disease on immediate and late outcome in a prospective series of LS patients. Methods: We performed a prospective analysis of 111 LS done between February 1993 and March 1999. The patients were classified by hematological indications into the following four groups: (a) group 1, low platelet count. This group was further subdivided into group 1A, idiopathic thrombocytopenic purpura (ITP) (n= 48) and group 1B, HIV-related ITP (n= 8); (b) group 2, anemia. This group was further subdivided into group 2A, autoimmune hemolytic anemia (n= 8), and group 2B, spherocytosis (n= 11); (c) group 3, malignancy (n= 28); and (d) group 4, others (n= 8). Immediate outcomes were recorded prospectively. Hematological status and late complications were reviewed after a mean follow-up of 24 ± 18 months. Results: There were no significant differences between the groups in terms of conversion, transfusion requirements, and morbidity, although transfusion and morbidity were slightly higher in group 3. However, hospital stay was significantly longer in groups 3 and 4 than in groups 1 and 2. Long-term follow-up showed satisfactory hematological results in ≥75% of patients (group 1A, 82%; group 1B, 88%; group 2A, 88%; group 2B, 100%; group 3, 75%; group 4, 88%). Overall, late morbidity was 8.3% and mortality was 6.2%, mainly due to deaths in group 4 (six of 22 patients). Conclusion: LS is a safe and reproducible procedure for most hematological indications, with a similar immediate outcome for benign diseases and a long-term hematological response comparable to the standard results that have been observed in open series. Received: 1 April 1999/Accepted: 22 November 1999/Online publication: 8 May 2000     

Abordaje conservador del embarazo ectópico cervical

Cervical pregnancy is a rare form of ectopic pregnancy with a high risk of hemorrhage. Early diagnosis is an important prognostic factor for survival and preserved fertility in these patients. We present the case of a patient diagnosed with cervical ectopic pregnancy in her seventh week of gestation. The therapeutic management was conservative and involved the combination of systemic and intra-amniotic methotrexate Because of the lower associated morbidity and mortality and the possibility of maintaining the patient’s fertility, conservative treatment is a viable therapeutic approach in cases such as that presented herein.